6-cyano steroidal enol ethers and process for preparing same



United States Patent 3,311,617 6-CYANO STEROIDAL ENOL ETHERS AND PROCESSFOR PREPARING SAP/IE Vladimir Petrow and John Patrick Yardley, London,England, assignors to The British Drug Houses Limited, London, EnglandNo Drawing. Filed June 18, 1954, Ser. No. 376,251 Claims priority,application Great Britain, June 20, 1963, 24,547/63 29 Claims. (Cl.260-43955) This invention is for improvements in or relating to organiccompounds, and has particular reference to 6-cyano steroidal enolethers.

It is an object of the present invention to provide the 6-cyanoderivatives of steroidal 3-enol ethers (derived from 4-en-3-oxosteroids) which may be represented (apart from substituents in Rings A,B, C and D and unsaturation in Rings B, C and D) by partial Formula Iwhere R is an alkyl, aralkyl or cycloalkyl radical containing up to 11carbon atoms.

The compounds of the present invention may be regarded as the 3-enolethers of 6-cyano-3-oxo-A -steroids. 6-cyano-3-oxo-A -steroids are wellknown to those skilled in the art on account of their biologicalproperties. In general, the biological properties of the 3-enol ethersof the present invention will resemble those of the corresponding6-cyano-3-oxo-A -steroids, but there will be quantitative differencesbetween them. Thus, for example, the 3-enol ethers of 6-cyano corticoidscan be more potent anti-inflammatory compounds than the corresponding3-oxo-A4-steroids. The 3-enol ethers of the pregnane and androstaneseries can have a more favourable progestational/anti-ovulatory ratiothan the corresponding B-ketones. Moreover the 3-enol ethers of theandrostane series can have enhanced anabolic/androgenic indices withrespect to the corresponding 3-ketones.

According to the present invention there is provided a process for thepreparation of a 3-enol ether of a 6-cyano- 3-oxo-A -steroid having inRings A and B of the steroid nucleus the structure where R is an alkyl,cycloalkyl or aralkyl radical containing up to 11 carbon atoms Whichprocess comprises reacting the corresponding 3-enol ether of a6-formyl-3- oxo-M-steroid, having in Rings A and B of the steroidnucleus the structure where R has the same meaning as above, withhydroxylamine to form an oxime having in Rings A and B of the steroidnucleus the structure IH NO H (III) where R has the same meaning asabove, and treating the oxime with a dehydrating agent.

3,311,617 Patented Mar. 28, 1967 The starting materials of the presentinvention are the corresponding 6-formyl enol ethers (II), thepreparation of which is described in our US. Patent No. 3,114,750. Thefirst stage of the present invention comprising the conversion of the6-formyl steroids into the corresponding oximes (III) may be carried outby treating the 6-forrnyl 3-enol ether with a slight excess over a molarequivalent of hydroxylamine hydrochloride and sodium acetate in anaqueous lower aliphatic alcohol. Alternatively, a Weakly basic solventsuch, for example, as pyridine may be employed. A variety of reactionconditions may be used; generally, a period of /z to 2 hours at 100 C.,or 12 to 24 hours at ambient temperature will lead to high yields of the6-hydroxyirninomethyl derivative (III). The products may separate fromthe reaction mixture as solids when the solution is cooled, or may beprecipitated from the mixture by dilution with water. The derivatives(III) may, if desired, be purified by crystallisation from a suitablesolvent in the usual manner.

Conversion of the hydroxyiminomethyl derivatives (III) into the 6-cyanoderivatives (I) may be achieved by contacting with a dehydrating agentconsisting of an acid anhydride under conditions to form anacyloxyiminomethyl enol ether having the partial formula CH=NOAeyl (IV)where R has the same meaning as above and heating to eliminate theelements of the corresponding acid. Thus,

for example, the acetoxyiminomethyl enol ether (IV) [where R is asdefined above and acyl is acetyl] may be prepared from thehydroxyiminomethyl enol ether (IH) by, for example, treatment withacetic anhydride in a weakly basic solvent such as pyridine. A widevariety of reaction conditions may be used. Thus the mixture may beheated to C. for a period of /2 to 2 hours, or it may be maintained atambient temperature for 12 to 48 hours. The product may be obtained bydiluting the reaction mixture with water, and either filtering, orextracting with a water-immiscible solvent. The product may, if desired,be purified by conventional procedures, or it may be, used in the crudestate for the following stage. The acetoxyiminomethyl enol ether may beheated in the dry state [in an inert atmosphere such, for example, asnitrogen if desired], at a temperature sufiicient to eliminate theelements of acetic acid and form the desired 6-cyano enol ether (I).This temperature will vary from compound to compound, and may bedetermined by noting the temperature at which elfervescence occurs; itwill generally be in the range of to 200 C. The reaction mayalternatively be carried out in solution in an inert, high boiling-pointsolvent such, for example, as diglyme, which is heated to its boilingpoint until reaction is complete, generally from 1 to 30 minutes.

lternatively, the two final stages may be carried out simultaneously.Thus the hydroxyiminomethyl enol ether (III) may be heated under refluxwith an acid anhydride and preferably with acetic anhydride, preferablyin an inert atmosphere and in the presence of a small quantity of, forexample, an alkali metal acetate. Conversion into the 6-cyano enol ether(1) will, in general, be complete Within 6 hours. The product may beobtained by pouring the cooled mixture into water and either filteringor extracting with a water-immiscible solvent.

The conversion of (III) into (I) may also be etfected by the use ofother dehydrating agents such for example as acid halides and inparticular, acetylchloride, thionyl chloride, phosphorus halides andparticularly phosphorus oxychloride (in organic solvents and in thepresence of bases such as pyridine if so desired). Other dehydratingagents include hydrogen chloride and polyphosphoric acid in an organicsolvent. The use of such dehydrating agents will naturally be avoided bythose skilled in the art when dealing with o-hydroxyiminomethylderivatives containing groups or residues susceptible to such reagents.The choice of method used will clearly depend on the nature of thesteroidal starting material.

The process of the present invention may be applied to a wide variety ofsteroidal starting materials of the androstane, 19-norandrostane(oestrane), pregnane, and 19-n0rpregnane series and their D-homoanalogues which may additionally be substituted in Rings A, B, C and Dand have unsaturation in Rings B, C and D. Thus the process isunaffected by the presence of 1) Hydroxyl groups and their acylderivatives and in particular by such groups at C C C C C C C C C and CIf such hydroxyl groups are acylated during the process of the presentinvention they may be regenerated by suitable hydrolytic procedures ifso desired.

(2) Alkyloxy groups, and in particular methoxy groups at C and C as wellas the cyclic ethers and esters derived from C C diols by reaction withcarbonyl compounds including acetone and substituted derivativesthereof.

(3) Alkyl groups, and in particular methyl groups at C1: C2: C91 C117C12: C14: C15, C16! C17, C18? C19 C20 and C21.

(4) Alkenyl and alkynyl groups, and in particular methylene andhalomethylene, cyclomethylene and halo and carboxy cyclomethylene,vinyl, ethynyl and substituted ethynyl groups particularly at C and CSubstituted ethynyl groups may include those in which the ethynylenichydrogen atom is replaced by alkyl, fluorine, chlorine, bromine,trifiuoromethyl and hydroxymethyl groups.

(5) Halogens, and in particular fluorine and chlorine at C9, C12, C16,C17 and C21 including C9, C11 dihalogen compounds.

(6) Hydroxyalkyl, alkyloxyalkyl, chloro and fiuoro alkyl groups forexample at C and C (7) Unsaturated linkages, and in particular doublebonds at 7 am 11, 12m ram 14, 15 C16: mzo

the grouping D o R" where R may be hydrogen, lower alkyl and aryl R maybe lower alkyl and aryl]. Certain carbonyl groups such, for example, asthose at C and C when present in the groupings will, in general,interfere with the process of the present invention and should beprotected and subsequently regenerated. Such protection may be affordedby standard methods such as prior conversion into the ethylene ketal,and in the case of the hydroxylated ketones, by conversion into l7ocandZl-acyl derivatives. The corticoid sidechain may be converted into a17aor 21-monoacyl, or a 17w, 21-diacyl derivative, or it may beconverted into a l7ot,20:20,2l-bismethylenedioxy derivative. In general,however, such protection will already have been efiected during thepreparation of the 6-formyl starting materials (see our U.S. Patent No.3,114,750) so that regeneration may be carried out at the completion ofthe process, if so desired.

The process of the invention may be used for the preparation of6-cyano-3-enol ethers derived, inter alia, from the following steroidal3-oxo-4-enes and acyl derivatives thereof and D-homo derivativesthereof:

Testosterone, 2-methyl testosterone, 17u-methyl, ethyl, vinyl, alkyl,butenyl, ethynyl testosterone, 17a-propynyl testosterone,17a-chlorethynyl, bromoethynyl, trifluoromethyl ethynyl testosterone andtheir 9(l1)-dehydro, ll-oxo and ll-hydroxy derivatives, and the 19-norderivatives thereof and the 17-ethers of the foregoing 17,3-hydroxycompounds Androst-4-ene-3,l7-dione and its Z-methyl, 16-methyl and2,16-dimethyl derivatives, and their ll-oxo, ll-hydroxy and the9(11)-dehydro derivatives 17a-acyloxy, 17nt-chloro and 17oz-fiuOI'O andl7a-rnethyl,

progesterone and their 7-dehydro, 9(l1)-dehydro, 12- dehydro, ll-oxo andll-hydroxy derivatives 16-methyl-17a-acyloxy progesterone and its9(11)-dehydro, ll-oxo and ll-hydroxy derivatives21-fluor0-l6-methyl-17a-acyloxy progesterone and their 9(11 )-dehydro,ll-oxo and ll-hydroxy derivatives 16-methylene and l6-halomethyle ne- 17a-acyloxy-progesterones and their 9(1l)-dehydro, ll-oxo and 11- hydroxyderivatives 16-ethylidene and16-haloethylidene-l7a-acyloXy-progesterones and the 9(11)-dehydro,ll-oxo and ll-hydroxy derivatives thereof 21-fluoro-16-methylene[halomethylene] 17a acyloxy progesterones and their 9(11)-dehydro,11-oxo and 11- hydroxy derivatives 16a,17a-isopropylidenedioxyprogesterone and its 9(11)- dehydro, ll-oxo and ll-hydroxy derivativesCortisone and hydrocortisone and their 16-methyl, 21- =methyl,16-methy1ene and 16-haloalkyl and 16-halomethylene derivatives andbismethylenedioxy derivatives thereof 16a-hydr0xy cortisone and16ec-hydroxyhydrocortisone and their condensation products with carbonylcompounds including the l6a,17o isopropylidenedioxy derivatives17ix,2l-dihydroxy progesterone and its 9(11)-dehydro derivative andbismethylenedioxy derivatives thereof The 16-methyl, ZI-methyll6-methylene and 16-halomethylene derivatives of l7ot,2l-dihydroxyprogesterone and their 9(11)-dehydro and bismethylenedioxy derivatives16a,17a,21 trihydroxypregna-4,9(l1)-diene-3,2O dione and its16a,17a-isopropylidenedioxy derivatives 21-fiuoro-17a-hydroxypregna-4,9(1 1)-diene-3,20-dione, its 16a-hydroxy derivative and the condensationproducts of the last compound with carbonyl compounds including acetone21-fluoro-17ot-hydroXypregn-4-ene-3,l1,20-trione, its

hydroxy derivative and the 16u,17u-acet0nide thereof 21-fluoro-ll,17a-dihydroxypregn-4-ene-3,20-dione, its 16cchydroxy derivative andthe 16a,17a-acetonide thereof 2l-fluoro-17a-acyloxyprogesteroneProgesterone and its 9(11)-dehydro, ll-oxo and ll-hydroxy derivatives16-methylprogesterone, l6a,l7ot-cyclornethylene progesterone, l6a,l7adihalocyclomethylene progesterone, 16u,17a-cycloethylidene progesterone,2l-fluoroprogesterone and 19-nor progesterone 21-hydr0xypregna-4,17-

Following is a description by way of example of methods of carrying theinvention into effect; the melting points reported were determined underB.P. conditions.

EXAMPLE 1 Preparation of I7/3-acet0xy-6-cyan0-3-methoxyandrosta-3,5-diene OAe Me O

A mixture of 17B-acetoxy-6-formyl-3-methoxyandrosta- 3,5-diene (1 g.),hydroxylamine hydrochloride (0.2 g.) and sodium acetate (0.4 g.) inethanol (40 ml.) and water 10 ml.) was stirred at room temperatureovernight. The solution was diluted with water and the precipitatedsolid was crystallised from chloroform-methanol to give 17,3acetxy-6-lzydr0xyiminomethyl-S-methoxyandrosta- 3,5-diene, M.P. 184-186" 0., decomp., [a] -266.3 (c., 1.3 in chloroform),

217 my (6 8,870) and 293 my. (6 21,580)

The foregoing oxirne was acetylated by treatment with acetic anhydrideand pyridine at room temperature for 48 hours. 17fi-acet0xy6-acet0xyimin0methyl-3-methoxyandrostra-3,5-diene formed rods frommethanol, M.P. 117.5 C., x] 212.4 (c., 1.0 in chloroform),

max.

224 my. (6 10,650) and 315 my (6 21,400

A solution of the foregoing product (1 g.) in diglyme ml.) was heated tothe boiling point for 2 minutes.

Dilution of the cooled solution with water and crystallisation of theprecipitated solid from chloroform-methanol gave175-acet0xy-6-cyan0-3-melh0xyandr0sta-3,5 diene, M.P. 197 C., [0;];147.7 (c., 1.0 in chloroform),

max.

'y 2225, 1639 and 1595 cmf The compound has claudogenic activity.

6. EXAMPLE 2 Preparation of 17,8-acet0xy-6-cyan0-3-meth0xy0estra-3,5-diene MeO- A mixture of hydroxylamine hydrochloride (5 g.), so diumacetate (10 g.), 17fl-acetoxy-6-formyl-3-methoxyoestra-3,5-diene (5 g.)and ethanol ml.) Was heated under reflux for /2 hour. Dilution withwater afforded a solid which was crystallised from methanol to give175-acetoxy-6-hydr0xyiminomethyl-3-meth0xy0estrw 3, S-diene as needles,M.P. 190191 C., decomp. [M 268 (c., 1.35 in chloroform) 1 218 III (68,590) and 294-5 111,. (e 21,220

A mixture of the foregoing product (2 g.), sodium acetate (anhydrous,0.25 g.) and acetic anhydride (35 ml.) was heated under reflux for 3hours. The cooled solution was poured into water and the precipitatedsolid was crystal lised from methanol to give17B-acetoxy-6-cyan0-3-meth- 0xy0estra-5',5-diene as lathS, M.P. 159 C.,[a];; -197 (c., 1.0 in chloroform) A 283 my (6 19,055)

max.

7mm 2220, 1640 and 1590 cmfi The compound has claudogenic activity.

EXAMPLE 3 Preparation of 21-acet0xy-6-cyano-1Ifi-formyloxy17nhydroxy-3-meth0xypregna-3,5-diene-Z0-0ne CIHZOAC CO ---0n OHC 0 Amixture of21-acetoxy-6-formyl-l1fi-formyloxy-17mhydroxy-3-methoxypregna-3,S-dien-ZO-one(7.05 g.), hydroxylamine hydrochloride (1.12 g.) and sodium acetate(2.25 g.) in ethanol ml.) and water (30 ml.) was heated under reflux for35 minutes. The cooled solution was diluted with water and theprecipitated solid was crystallised from chloroform-methanol to giveZI-acetoxy- 11l8-formyloxy-l7a-hydroxy-6 hydroxyiminomethyl 3-methoxypregna-3,5-dien-20-0ne, M.P. 210-218 C. decomp. [a] 2l.8 (c., 1.0in chloroform) A 216 my (6 9,830) and 294 my (6 21,140)- A solution ofthe foregoing oxime (2 g.) was treated with acetic anhydride andpyridine at room temperature overnight. The mixture was poured intowater, the precipitated solid was collected, washed with water anddried. It was then heated, under nitrogen, to C. for 2 minutes.crystallisation of the residue from chloroformmethanol gave 21acet0xy-6-c'yano-1Zfi-formyloxy-J7ahydroxy 3 methoxypregna 3,5 dz'en 20one as MeO- l ON

A solution of 21-acetoxy-11B-formyloxy-l7a-hydroxy-6-hydroxyiminomethyl-3-methoxypregna-3,5 dien 20- one (prepared asdescribed in Example 3) (1 g.) and sodium acetate (0.05 g.) in aceticanhydride (50 ml.) was heated under reflux for 2% hours under nitrogen.The solid obtained on pouring the cooled mixture into water wascrystallised from chloroform-methanol to give 6-cyano-I7a,21-diacet0:cy-1Ifi-farmyloxy 3 methoxypregna-3,5-dien-20-aneas feathery needles, M.P. 263.5 C.,

[011 -57.2 (c., 0.5 in chloroform) max.

11 2195, 1623 and 1588 cmf The compound has claudogenic activity.

EXAMPLE 5 Preparation of 21 -acetxy-6-cyano-1 7 a-lzydroxy-3methoxypregna-3,5,9(11 )-trien-20-one C H1OAC A solution of 21 acetoxy6-f0rmyl-17a-hydroXy-3- methoxypregna-3,5,9(11)-trien-20-one (3.65 g.),hydroxylamine hydrochloride (0.63 g.) and sodium acetate (1.25 g.) inethanol (60 ml.) and water (25 ml.) was heated under reflux for 35minutes. The mixture was diluted with water and the precipitated solidwas crystallised from chloroform-methanol to give21-acet0xy-17a-hydr0xy-6- hydroxyimin0methyl-3'methoxypregna3,6,9(11)-trien- 20-one as prisms, M.P. 226234 C. decomp. [@1 133.4 (c.,1.22 in chloroform P 293 mu (6 20,490)

max.

The foregoing oxime was acetylated by treatment with acetic anhydrideand pyridine at room temperature for 2 days.21-acet0xy-6-acetoxyimin0methyl-17u-hydroxy- 3-methoxypregna 3,5,9(1I)trien-ZO-one formed prisms from chloroform-methanol, M.P. 176 C. decomp.[041 -143.9 (c., 104 in chloroform) A 223 mp. (6 11,930) and 313 mu20,170)

The foregoing product was heated under nitrogen at 160 C. for 2 minutes.Crystallisation of the residue 8 gave 21acet0xy-6-cyan0-17u-hydr0xy-3-methoxypregna- 3,5,9(11)-trien-20-0ne asrods, M.P. 212 C. decomp., [04, 95.7 (c., 0.55 in chloroform) A553? 283my (5 17,740), 11 2195, 1624 and 1592 (ml- The compound is of value asan intermediate in the preparation of substances having antiendotoxicand antiinfiamrnatory activity.

EXAMPLE 6 Preparation of 6-cyarzo-3-ethoxy-16aJ7a-is0pr0pylideneai0xy-pregna-3,5-dien-ZO-one Eto- A solution of3-ethoxy-6-formyl- 16a, 17a-isopropylidene-dioxypregna-3,5-dien-20-one(5 g.), sodium acetate (2.2 g.) and hydroxy-lamine hydrochloride (1.1g.) in ethanol (37.5 ml.) and water (7.5 ml.) was heated under refluxfor 35 minutes. The solid which separated from the cooled mixture wascrystallised from ethanol to give 3-eth0xy-6-hydr0xyimin0-methyl-16a,17a-isopropylidenedioxypregna-3,5-dien-20-one as prisms, M.P. 219-224" C.decomp., (c., 0.85 in chloroform) EtOH mnx.

219 mp. (e 8,970) and 29 1 mu (6 20,960)

The foregoing product was acetylated by heating it in acetic anhydrideand pyridine at 100 C. for 1 hour. 6 acetoayz'minomethyl 3-eth0xy :,170:isopropylidenedioxypregna-3,5-dien-20-0ne formed needles from ethanol,M.P. 186188 C., 112 (c., 0.85 in chloroform) has? 224.5 me (6 10,140)and 315 mu (6 19,680)

The foregoing product (2 g.) was heated to C. until gas evolutionceased. The residue was crystallised from ethanol to give6-cyano-3-ezh0xy-16a,17u-is0pr0- pylidenedi0xypregna-3,5-dien-ZO-one asneedles, M.P. 223-226 C., -71.2 (c., 0.65 in chloroform) A 284 my (619,520)

The last compound was also prepared from the 6-hydroxyiminomethylderivative by heating it (2 g.) and anhydrous sodium acetate (0.25 g.)in acetic anhydride (35 ml) under reflux for 3 hours. The cooled mixturewas poured into water and the precipitated solid was crystallised fromethanol to give the 6-cyano compound, M.P. 223-226 C.

The compound has anti-inflammatory, progestational and antiendotoxicactivity.

EXAMPLE 7 Preparation of 17a-acetoxy-6-cyan0-3-meth0xypregna-3,5-dien-20-0ne O OMe A solution of17a-acetoxy-6-formyl-3-rnethoxypregna- 3,5-dien-20-one (0.75 g.),hydroxylamine hydrochloride (0.14 g.) and anhydrous sodium acetate (0.28g.) in ethanol (13 ml.) and water (3 ml.) was heated under reflux for 30minutes. The solution was cooled, poured into water and the precipitatedsolid was crystallised from methanol to give17u-acetoxy-6-hydroxyimin0methy[-3- methoxypregna 3,5 dien 20 one, M.P.175-180 C., [(21 204 (c., 1.0 in chloroform).

A solution of the foregoing oxime (0.5 g.) and anhydrous sodium acetate(0.06 g.) in acetic .anhydride (9 ml.) was heated under reflux for 3hours and poured into ice-water. The precipitated solid was crystallisedfrom methanol to give 17a-acetoxy-6-cyano-3-meth0xypregnd- 3,5dien-20-one as plates, M.P. 266.5" C., [a] 156.6 (c., 1.0 in chloroform)A222? 282 m =18,630) The compound has progestational activity.

EXAMPLE 8 Preparation of 1 7 ot-chl0rethynyZ-6-cyan0-1 7 fi-hydroxy-3-171ethoxyoestra-3,5-a'iene 219-220 my. (e 10,010) and 322 m, (616.500)

A solution of 17u-chlorethynyl-6-formyl-17,8-hydroxy-3-methoxyoestra-3,5-diene (0.28 g), hydroxylamine hydrochloride (0.28g.) and sodium acetate (0.2 g.) in ethanol (8 ml.) and water (2 ml.) washeated under reflux for 35 minutes. The solid obtained on pouring themixture into water was crystallised from aqueous methanol to give17ot-chl0retlzynyl-17B-hydr0xy 6hydroxyiminomethyl-3-meth0xy0estra-3,5-diene as rods, M.P. 140 C.,decomp., [a] 323 (c., 0.25 in chloroform) The foregoing oxime wasacetylated by treatment with acetic anhydride and pyridine at 100 C. for1 hour. The solid obtained on dilution with water was collected, washedand dried and heated, under nitrogen, to 160 C. for 2 minutes. Theresidue was crystallised from aqueous methanol to give17ot-chlorethynyl-6-cyan0-17B-hydroxy- 3-mezhoxyoestra-3,5-diene asprisms, M.P. 250-259 C., decomp, [0th, 289 (c., 0.15 in chloroform)A522} 283 my (6 18,480)

The compound has claudogenic and progestational activity.

max.

1 0 EXAMPLE 9 Preparation of 1 7 a,20120,2] -bismerhylenedioxy-6-cyano3-etlz0xypregna-3,5-dien-1l-one 281 m (6 19,500 P5 1 2230, 1640, 1600cmf The compound may be converted into the corresponding corticoidaltype by regeneration of the dihydroxyacetone side chain.

max.

EXAMPLE 10 Preparation of 1 7 a-aceZ0xy-6-cyan0-3 -meth0ucy-1 6-methylenepregna-3,5-dien20-one T Me 5 JN 17a acetoxy 6 formyl 3 methoxy16 methylenepregna-3,5-dien-20-one (0.75 g.), hydroxylaminehydrochloride (0.14 g.) and sodium acetate (0.28 g.) Were refluxed inethanol (13.2 ml.) and water (3.3 ml.) for /2 hour. The solid obtainedon pouring the mixture into water was crystallised from methanol to giveUna-acetoxy- 6 hydroxyimz'nomethyl 3 methoxy 16 methylenepregna 3,5 dien20 one as prisms, M.P. 1738 C., [a] 309 (c., 0.76 in chloroform) W 294.my (E=20,220)

A solution of the foregoing product (0.5 g.) and sodium acetate (0.06g.) in acetic anhydride (8.75 ml.) was heated under reflux for 3 hours.The mixture was poured into water and the precipitate was crystallisedfrom methanol to give 17a-acet0xy-6-cyan0-3-methoxy-16-methyleneprena-3,5-dien-20-one as needles, M.P. 232 C., [111 -236" (c., 1.0 inchloroform) 7mm 2210, 1630 and 1595 cmf The compound has progestationaland anti-ovulatory properties.

EXAMPLE 11 CHzOAC MeO Preparation of p- (6-cyano-3 -ethxy-17fi-hydr0xyandr0sta- 3,5 -dien-1 7 01-3 1 -propionic acid lactone 0 IMA."

A solution of [3(3-ethoxy-6-formyl-17,8-hydroxyandrosta-3,5-dien-17a-yl)-propionic acidlactone (1 g.), anhydrous sodium acetate (0.5 g.) and hydroxylarninehydrochloride (0.25 g.) in ethanol ml.) and water (2 ml.) was heatedunder reflux for 45 minutes. The product obtained on pouring the mixtureinto water was washed, dried and heated under reflux for 3 hours inacetic anhydride (1.5 ml.) containing sodium acetate (0.1 g.) The cooledmixture was poured into ice-water, and the product crystallised to give{3-(6-cyano-3-ethoxy- 1 7 fi-hyd r0xyandrosta-3 ,5 -d ien-I 7 a-yl-pr0pi0n ic acid lac tone with A 284 m (6: 19,600), 'y 2225, 1635 and1600 cmf The compound has diuretic activity.

EXAMPLE 13 Preparation of 6-cyano testololactone 3-enol methyl etherMeO- I ON

A solution of 6 formyltestololactone 3-enol methyl ether (1.8 g.),sodium acetate (0.7 g.) and hydroxylamine hydrochloride (0.3 g.) inethanol (30 ml.) and water (7 12 ml.) was heated under reflux for 45minutes. The mixture was poured into water and the product crystallisedto give 6-hydroxyiminomethyltestololactone 3-en0l methyl ether.

A solution of the foregoing oxime (1 g.) and anhydrous sodium acetate(0.075 g.) in acetic anhydride (15 ml.) was heated under reflux for 3hours. The product obtained on pouring the mixture into water wascrystallised to give 6-cyanotest0lolact0ne 3-en0l methyl ether, Amax.283 mp. (=19,-450 7mm 2230, 1635, 1595 cmr EXAMPLE 14 Preparation ofacetoxy 6 cyano-I6-ethylia'ene-3- methoxypregna-3,5-dien-20-0ne Asolution of 17a acetoxy-l6-ethylidene-6-tormyl-3-meth0xypregna-3,5-dien-20-one (1.5 g.), sodium acetate (0.75 g.) andhydroxylaniine hydrochloride (0.3 g.) in ethanol (30 ml.) and water (7ml.) was heated under reflux for 35 minutes. The mixture was poured intowater, and the product purified to give 17a acetoxy 16 ethylidene6-hydroxyimin0methyl-3-meth0xypregna-3,5-dien- 20-0ne.

A solution of the above compound (0.75 g.) and anhydrous sodium acetate(0.1 g.) in acetic anhydride (10 ml.) was heated under reflux for 2hours. The product obtained on pouring the mixture into water wascrystallised, giving 17a acetoxy 6cyano-J6-ethylidene-3-meth0xypregna-3,5-dien-20-0ne, A 284 mp.(e=19,500), 7mm 2230, 1640, 1600 cm.'-

The compound has anti-fertility activity.

EXAMPLE 15 Preparation of 6 cyano 3 ethoxy-I75-pr0pi0n0xy-17uprop-1'-ynyl androsta-S' ,5 -diene 0.0 0.011% 05o .Me

EtO-

A solution of 3 ethoxy-6-formyl-17fl-propionoxy-1711- (prop-1'ynyl)androsta-3,5-diene (0.75 g.), hydroxylamine hydrochloride (0.2 g.)and sodium acetate (0.4 g.) in ethanol (15 ml.) and water (4 ml.) washeated under reflux for 30 minutes. The mixture was poured into water,and the precipitate filtered and purified to give 3- ethoxy 6hydroxyiminomethyl 1713 pr0pi0n0xy-17a- (prop-1 -ynyl)andr0sta-3,5-diene.

The foregoing compound (0.5 g.) and anhydrous sodium acetate (0.1 g.) inacetic anhydride (10 ml.) was heated under reflux for 3 hours. Theproduct obtained on pouring the mixture into water was crystallised,giving 6 cyano 3 ethoxy 176 propionoxy 17oz (prop- 1 ynyl)andr0sta 3,5diene, A 282 m (6, 19,200), A max 2230, 1640 and 1600 cmf The compoundhas progrestational activity.

1 3 EXAMPLE 16 Preparation of6-cyan0-11a,I7B-diacetoxy-3-methoxyandrosta-S ,5 -diene AcO-- MeO- Asolution of 11a,17 3-diacetoxy-6-formy1-3-methoxyandrosta-3,5-diene (2.5g.), sodium acetate (1 g.) and hydroxylamine hydrochloride (0.5 g.) inethanol (30 ml.) and water (6 ml.) was heated under reflux for 45minutes. The mixture was poured into water, and the precipitate of crudeoxime was filtered, washed and dried. It was heated under reflux for 3hours with acetic anhydride (25 ml.) containing sodium acetate (0.15g.). The cooled mixture was poured into ice-water, and the precipitatecrystallised giving6-oyano-Z1a,175-diacetoxy-3-methoxyandrosta-3,5-diene, A 283 m(e=19,480), 7,11. 2230, 1635 and 1600 cm.-

The compound has anabolic and androgenic activity.

EXAMPLE 17 Preparation of ethyl 6-cyano-3-etIzoxypregna-3,5,17(20)-trierz-ZI-oate EIJELC O Et EXAMPLE 18 Preparation of I7fl-acetoxy-3-benzyloxy-6-cyanoandr0sta- 3,5-diene EtO- A solution of17B-acetoxy-3-benzyloxy-6-formylandrosta'3,5-diene (1 g.), hydroxylaminehydrochloride (0.2 g.), and sodium acetate (0.5 g.) in ethanol (20 ml.)and water ml.) was heated under reflux for 30 minutes.

14 The mixture was poured into water, and the precipitate filtered andcrystallised to give 17fi-acetoxy-3-benzyloxy-6-hydroxyiminomethylandrosta-3,5-diene.

A solution of the foregoing oxime (0.5 g.) and anhydrous sodium acetate(0.1 g.) in acetic anhydride (8 ml.) was heated under reflux for 3 /2hours. The mixture was poured into water, and the product collected andcrystallised to give 17,8-acetoxy-3-benZyloxy-6-cyanoandrosta-3,5-diene,Amax' 283 III/1. (e:19,000), 'y 2230, 1635 and 1595 cmf The compound hasanabolic and androgenic activity.

EXAMPLE 19 Preparation of 6-cyano-3-ethoxy-25D-spir0sta-3,5-diene Asolution of 3-ethoxy-6-forrnyl-25D-spirosta-3,S-diene (5 g.), sodiumacetate (2.5 g.) and hydroxylamine hydrochloride (1.2 g.) in ethanol (40ml.) and water (10 ml.) was heated under reflux for minutes. The mixturewas poured into water, and the product collected and crystallised togive 3-etlzoxy-6-hydroxyiminomethyl-ZSD- spir0sta-3,5-diene.

A solution of the foregoing oxime (2 g.) and anhydrous sodium acetate(0.25 g.) in acetic anhydride (40 ml.) was heated under reflux for 3hours. The mixture was poured into ice-water, and the product filteredand crystallised to give 6-cyano-3-ethoxy-Z5D-spir0sta-3,S-diene withAmax' 282 m (e=18,500), 2225, 1640 and 1600 cmf EXAMPLE 20 Preparationof 1 7 ,8-acetoxy-6-cyano-3 -ethoxy2 ocmet/1ylana'rosta-3,5-diene Asolution of 17fi-acetoxy-3-ethoxy-6-formyl-2txmethylandrosta-3,5-diene(1.5 g.), sodium acetate (0.75 g.) and hydroxylamine hydrochloride (0.3g.) in ethanol (3-5 ml.) and water (8 ml.) was heated under reflux for 1hour. The mixture was poured into water, and the product crystallised togive17fl-acetoxy-3-eth0xy-6-hydroxyiminOmeflzyZ-Za-methylandr0sta-3,5-diene.

A solution of this oxime (1 g.) and anhydrous sodium acetate (0.05 g.)in acetic anhydride (12 ml.) was heated under reflux for 3 /2 hours. Themixture was poured into water, and the product purified to give17(3-acetoxy-6- cyana-3-eth0xy-2a-methylandr0sta-3,5 -diene, A 281 m(e=18 500), 7mm 2225, 1640 and 1600 cmr The compound has anabolic andandrogenic activity.

EXAMPLE 21 Preparation of 6-cyan0-16a,1 7a-cyclomethylene-3-metlzoxypregna-3,5-dien-20-0ne Me O A solution of16a,17a-cyclomethylene-6-formyl-3- methoxypregna-S,S-dien-ZO-one (1.1g.), sodium acetate (0.45 g.) and hydroxylamine hydrochloride (0.25 g.)in ethanol (10 ml.) and water (1.5 ml.) was heated under reflux for 35minutes. The cooled mixture was poured into water, and the productcrystallised to give 16a,17a cyclomezhylene 6 hydroxyiminomethyl 3-metlzoxypregna-3,5-dien-20-0ne.

A solution of the above oxime (0.5 g.) and anhydrous sodium acetate(0.05 g.) in acetic anhydride (7 ml.) was heated under reflux for 3hours. The mixture was poured into water, and the product filtered andcrystallised to give 6 cyano-l 60:,1 7a-cyclomelhylene-3-methoxypregna-3,5-dien-20-0ne, with X 282 m (e=18,750), 'y 2225, 1630 and 1595 cm.-

The compound has anti-fertility activity.

EXAMPLE 22 Preparation 1 7a-acet0xy-6-cyan0-3 -meth0xy-1 6wmethylpregna-3,5-dien-20-0ne A solution ofl7a-acetoxy-6-formyl-3-methoxy-l6amethylpregna-S',5-dien-20-0ne (0.8g.), hydroxylamine hydrochloride (0.25 g.) and sodium acetate (0.5 g.)in ethanol (15 ml.) and water (4 ml.) was heated under reflux for 30minutes. The mixture was poured into water, and the product filtered,washed and dried. Its solution in acetic anhydride (25 ml.) containingsodium acetate (0.1 g.) was heated under reflux for 3 hours, cooled, andthe mixture poured into ice-water. Crystallisation of the product gave17a-acetoxy-6-cyan0-3-methoxy-l6a-methylpregna-3,5-dien-20-0ne, A 283my. (e=18,050), 7mm 2220, 1630 and 1595 crnf I The compound hasprogestational and anti-fertility activity.

16 EXAMPLE 23 Preparation of 208-acetoxy-6-cyano-3ellz0xypregna-3,5-diene EtO Preparation of6-cyalz0-3-ethoxy-17/8-propri0n0xy-17avinylandr0sta-3,5-diene O C OC2115 I ON A solution of 3-ethoxy-6forrnyl-17B-propionoxy-17avinylandrosta-3,5-diene (3 g.), hydroxylaminehydrochloride (0.6 g.) and sodium acetate (1.5 g.) in ethanol (60 ml.)and water (15 ml.) was heated under reflux for 1 hour. The mixture waspoured into water, and the precipitated solid was filtered, washed anddried. Its solution in acetic anhydride (30 ml.) containing sodiumacetate (0.1 g.) was heated under reflux for 3 /2 hours, cooled, and themixture poured into cold water. The product was crystallised to give6-cyarr0-3-eth0xy-17/3- propionoxy-l7a-vinylandr0sta-3,5-diene, A 281 mu(s=l9,000), 'y 2220, 1640 and 1590 cmr The compound has anabolic andandrogenic activity.

A solution of17,6-acetoxy-3-ethoxy-6-formyl-17a-methylandrosta-3,5-diene (5 g.) andhydroxylamine hydro- A 219.5 111 .1 (6 8,980) and 295 my (6 21,110)

The foregoing compound (3 g.) and anhydrous sodium acetate (0.6 g.) inacetic anhydride (100 ml.) was heated under reflux for 3 hours. Theproduct obtained on pouring the mixture into water was crystallised,giving 171-3- acetoxy 6-cyano-3-eth0xy-17a-methylandr0sta-3,5-diene,

M.P. 164-165 C., [01], 130 (6, 1.0 in chloroform),

max.

v 2193, 1631 and 1591 cm.

The compound has anabolic/ androgenic activity.

EXAMPLE 26 Preparation of 17a-acet0xy-3-eth0xy-6-cyanopregna-3,5,7-trien-20-one O OMe EtO A solution of17a-acetoxy-3-ethoxy-6-forrnylpregna- 3,5,7-trien-20-one (1.07 g.),sodium acetate (0.44 g.) and hydroxylamine hydrochloride (0.22 g.) inethanol (7.5 ml.) and water (1.5 ml.) was heated under reflux for 35minutes. The mixture was filtered whilst hot, and the solid whichseparated from the cooled filtrate was crystallised fromchloroform-ethanol to give I7a-aCEtOXy-3-ethoxy-o-hydroxyiminomethylpregna-3,5,7-trien-20-0ne as prisms, MP. 241244" C. decomp, [011 55.7 (c., 0.95 in chloroform) 1 240.5 Ill/.L (e14,130) and 342 III/.1 (6 18,150),

vgg gf 3586, 1736, 1731, 1714, 1644, 1614 and 1590 cm (a) The foregoingproduct was acetylated in acetic anhydride and pyridine at 25 C. for 16hours. 17w acetoxy-6-acet0xyiminomethyl-3-ethoxypregna-3,5,7-lrie71-20-0ne formed prisms from ethanol, M.P. 160164 C. decomp.

1 240 m (=13,680) and 302 m 6:16340 The foregoing compound was heated at175 C. until evolution of gases ceased. The residue was crystallisedfrom ethanol to give 17a-acetoxy-3-ethoxy-6-cyan0pregna-3,5,7-Irien-Z0-0ne, M.P. 215-216 C., [04 65 (c., 1.1 in CHClg),

x3312 227.5 m (e =s,720) and 350 m (6 =15,800)

1 23 was then washed with 5% potassium hydroxide solution, water toneutrality, dried and evaporated in vacuo to give a gum which uponcrystallisation from acetone'hexane gave I7a-acetoxypregna-4,6-diene-3,20-di0ne as rods, M.P. 210222 C., [07],+14.5 (c., 10.2 in chloroform),

212? 283 m (6 20,785) 5,39 1732, 1715, 1658, 1619, 1583 mm The foregoingcompound (1.12 g.) in dry benzene (25 ml.) with triethylorthoformate (1ml.) and ethanol (1 ml.) was treated with toluene-p-sulphonic acid (50mg.) and heated under reflux for 2 hours. Pyridine (1 ml.) was thenadded, the mixture twice washed with water (25 ml.), dried andevaporated in vacuo. The gummy product was purified from ethanol andthen acetone to give 17cc acetoxy 3 eth0xypregna-3,5,7-trien-ZO-one asrods, M.P. 216-222 C., [121 167.3 (c., 0.75 in chloroform containing0.2% pyridine),

A1122? 214215 m (6 7,388), 322 m (5 18,590)

and

331 1743, 1722, 1645, 1620 cmr A mixture of dimethylformamide (1.6 ml.)and ethylene dichloride (6.6 ml.) was cooled to 0 C. and treateddropwise whilst stirring during 15 minutes, with a solution of phosgene(13.3 ml. of 10%-redistilled ethylene dichloride). The mixture wasstirred a further 10 minutes and a solution of17a-acetoxy-3-ethoxypregna-3,5,7-trien- 20-one (1.7 g.) in ethylenedichloride (8 ml.) added. The mixture was allowed to attain roomtemperature whilst stirring for 2 hours. It was then poured into amixture of sodium acetate (2.7 g.) in water (4 ml.) and methanol (16ml.), diluted with ether, the third layer washed with sodium hydrogencarbonate solution and this with water to neutrality. After drying, thesolvents were removed under reduced pressure and the residuecrystallised from ethanol to give 17a acetoxy 3 ethoxy-6-f0rmylpregna-3,5,7-trien-20-0ne as needles, M.P. 184-189 C., [111 56.7 (c., 1.05 inchloroform) w 218 m (6 10,900), 272 my. E 10,620) and 383 m ax.

7355; 1742, 1722, 1e50, 1663, 1614. and 1601 mm EXAMPLE 27 Preparationof 21-acet0xy-6-cyan0-1 16,1 7 a-dihydrOIy-Emet/z0xypregna-3,5-dien-20-0ne C H: 0 Ac P 213 m (5 10,050) and 290 my.(5 21,090)

max.

A532 282 m (6 19,560) The compound has anti-endotoxic andanti-inflammatory properties.

EXAMPLE 28 Preparation of 21-acet0xy-6-cyan0-l 7 oc-h yd ran-3methoxypregna-EJ ,5 -diene-I 1,20-dine 0 moan ---orr o q A solution of2l-acetoxy-6-formyl-l7a-hydroxy-3-methoxypregna-3,5-diene-11,20-dioneg.), hydroxylamine hydrochloride (1.67 g.) and sodium acetate (3.34 g.)in ethanol (150 ml.) and water (50 ml.) was heated under reflux forminutes. The cooled solution was poured into water and the precipitatedsolid was collected, washed with water and dried. It was acetylated withacetic anhydride and pyridine at 100 C. for 1 hour. The solid obtainedon dilution with water was collected, washed with water, dried andheated, under nitrogen, to 180 C. for 2 minutes. Crystallisation of theresidue'from aqueous methanol gave 21 -acet0xy-6-cyan0-I 7a-hydroxy-3-mcrlzoxypregna-3,5-diene-11,20-di0ne as prisms, M.P. 2l5.5 C., 5.6 (c.,2.05 in chloroform),

A3523? 283 m (e 18,250) The compound has anti-inflammatory properties.

EXAMPLE 29 Preparation of6-cyan0-170:,21-diacet0xy-3-r71ethoxypregrza-3,5-dien-ZO-one CHzOAo C O)w-O Ac Me MeO- 20 3-mell:oxypregna-3,5-dien-20-0ne as blades, M.P. 144C., [04 -128 (c., 0.55 in chloroform),

A solution of the foregoing product (5.35 g.) in dichloromethane (15ml.) was added at 0 C. to a suspension of the Vilsmeier reagent preparedfrom phosphoryl chloride (1.4 ml.) and dimethylformamide (4.4 ml.) indichloromethane (25 ml.) and the mixture was stirred at 0 C. for 1%hours. After the addition of 10% aqueous sodium acetate ml.) the productwas isolated with ether and crystallised from methanol to give17a,2I-diacetoxy 6 j0rmyl-3-methoxypregna-3,5-dien-20-0ne as plates,M.P. 177 C., [a];; 131 (c., 1.0 chloroform),

i532? 219.5 m (6 9,880) and 321 mp. (6 14,410)

A solution of the foregoing product (2 g.), hydroxylamine hydrochloride(0.3 g.) and sodium acetate (0.6 g.) in ethanol (30 ml.) and water (8ml.) was heated under reflux for 40 minutes. The precipitate obtained onpouring the mixture into water was crystallised from methanol to give:,2I-diacet0xy-6-hydroxyiminometlzyI-3-mezltoxypregna-3,5-dien-20-0ne asneedles, M.P. 250 C., [(11 3 l81 (c., 1.0 in chloroform),

A522? 294 m (5 20,160) and 218.5 111 1. (6 9,100)

A solution of the foregoing oxime (1.3 g.) and anhydrous sodium acetate(0.2 g.) in acetic anhydride (20 ml.) was heated under reflux and undernitrogen for 2% hours. The solid which separated on cooling wascrystallised from methanol to give6-cyano-17a,21-diacetoxy-3-methoxypregna-3,5-dien-20-one as needles,M.P, 253 C., [0:] 127 (c., 1.3 chloroform),

The compound is of value as an intermediate for the preparation ofcortical steroid types.

We claim:

1. A process for the preparation of a 3-enol ether of a 6-cyano-4-oxo-Asteriod having in Rings A and B of the steroid nucleus the structurewhere R is an alkyl, cycloalkyl or aralkyl radical containing up to 11carbon atoms which process comprises reacting the corresponding 3'-enolether of a 6-formyl-3-oxo-A steroid, having in Rings A and B of thesteroid nucleus the structure CHO (II) where R has the same meaning asabove, with hydroxylamine to form an oxime having in Rings A and B ofthe steroid nucleus the structure 21 form an acyloxyiminomethyl enolether having the partial structure H=NOAcyl (IV) where R has the samemeaning as above and heating to eliminate the elements of thecorresponding acid.

4. A process as claimed in claim 3 wherein the acyloxyiminomethyl enolether is heated in the dry state in an inert atmosphere.

5. A process as claimed in claim 1 wherein the oxime is converteddirectly into the corresponding 3-enol ether of a 6-cyano-3-oxo-A-steroid by heating under reflux with an acid anhydride in an inertatmosphere in the presence of a small quantity of an alkali metalacetate.

6. 3-enol ethers of 6-cyano-3-oxo-A -steroids of the androstane,19-norandrostane, pregnane and 19-norpregnane series having in Rings Aand B of the steroid nucleus the structure where R is an alkyl, aralkylor cycloalkyl radical containing up to 11 carbon atoms.

7. 17 6-acetoxy-6-cyano-3-methoxyandrosta-3,S-diene.

8. 17f3-acetoxy-6-cyano-3-methoxyoestra-3,S-diene.

9. 21 acetoxy 6 cyano 11,3 formyloxy 17chydroxy-3-methoxypregna-3,5--dien-20-one.

10. 6 cyano 17a,21 diacetoxy 115 formyloxy 3-methoxypregna-3,S-dien-ZO-one.

11. 2l-acetoxy-6-cyano 17mhydroxy-3-rn-methoxypregna-3,5,9(1l)trien-20-one.

12. 6-cyan0 3 ethoxy-l6u, pregna-3,5-dien-20-one.

13. 17a-acetoxy-6-cyano 3 methoxypregna-3,5-dien- 20-one.

14. 170: chlorethynyl 6 cyano 17,3 hydroxy 3- methoxyoestra-3,5-diene.

15. 17a acetoxy 6 cyano 3 methoxy 16-methylenepregna-3,S-dien-ZO-one.

16. 21 acetoxy 6 cyano 3 methoxypregna 3, 5,l7(20)-trien-1l-one.

17. B (6 cyano 3 ethoxy 17,8 hydroxyandrosta- 3,5-dien-17a-yl)-propionicacid lactone.

18. 6 cyano 3 ethoxy 175 propionoxy 17a-(prop-l-ynyl)-androsta-3,5-diene.

19. 6 cyano 3 ethoxy 25D spirosta 3,5-diene.

20. 17,8-acetoxy 6 cyano 3 ethoxy Zea-methylandrosta-3,5-diene.

21. 6 cyano 160:, 17a cyclornethylene 3 methoxypregna-3,5-dien-20-one.

22. 17a acetoxy 6 cyano 3 methoxy 16amethylpregna-3,S-dien-ZO-one.

23. 17,8 acetoxy 6 cyano 3 ethoxy 17a-methylandrosta-3,5-diene.

24. 17a acetoxy 3 ethoxy 6 cyanopregna 3,5,7- trien-20-one.

17a-isopropylidenedioxy- 25. 21 acetoxy 6 cyano 11/3, 1711 dihydroxy-3-methoxypregna-3,S-dien-ZO-one.

26. 21 acetoxy 6 cyano 17a hydroxy 3 methoxypregna-3 ,S-diene-l1,20-di0ne.

27. 6 cyano 17a, 21 diacetoxy 3 methoxypregna- 3,5-dien-20-one.

28. A compound of the formula RO V R: 1 Re I ON wherein R is an alkyl,aralkyl or cycloalkyl radical containing up to 11 carbon atoms, R ishydrogen or methyl, R is 0x0, hydrogen, hydroxy or lower alkanoyloxy, Ris COCH --COCH OH, COCH O(lower alk-anoyl, =CHCH O(1ower alkanoyl),CHCOO (lower alkyl) or CH([-3-lower 'alkanoyloXy)CI-I R is hydrogen,hydroxy or lower alkanoyloxy, and R is hydrogen, lower alkyl or loweralkylidene, or R and R together are 16a,l7a-isopropylidenedioxy or16a17a-cyclomethylene, and wherein the bronen line between positions 7and 8 represents an optional double bond and the broken line betweenpositions 9 and 11 represents an optional double bond when R is a singlehydrogen atom.

No references cited.

ELBERT L. ROBERTS, Acting Primary Examiner.

6. 3-ENOL ETHERS OF 6-CYANO-3-OXO-$4-STEROIDS OF THE ANDROSTANE,19-NORANDOSTANE, PREGNANE AND 19-NORPREGNANE SERIES HAVING IN RINGS AAND B OF THE STEROID NUCLEUS THE STRUCTURE